Arachidonate 5-lipoxygenase


Arachidonate 5-lipoxygenase

Arachidonate 5-lipoxygenase (5-lipoxygenase, 5-LO or Alox5) is a human enzyme, member of the lipoxygenase family. It transforms EFAs into leukotrienes and is a current target for pharmaceutical intervention in a number of diseases.

ubstrates and products

EFA substrates and leukotriene products of 5-LO include:
* Arachidonic acid (AA) yields the 4-series leukotrienes (LTB4, LTC4, LTD4, LTE4 — generally proinflammatory)
* Eicosapentaenoic acid (EPA) yields the 5-series (LTB5, LTC5, LTD5, LTE5 — antiinflammatory)
* Gamma-linolenic acid (GLA "via" the DGLA intermediary) yields no leukotrienes, but inhibits the conversion of AA.

Functions

5-LO catalyzes oxidation of AA at the 5-position to yield 5-hydroperoxyeicosatetraenoic acid (5-HPETE). 5-LO then converts 5-HPETE to leukotriene A4. [Reaction [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R01595 R01595] and [http://www.genome.ad.jp/dbget-bin/www_bget?rn+R03058 R03058] at KEGG Pathway Database.]

Two other lipoxygenases, 12-LO and 15-LO, act at the 12- and 15-positions, yielding 12- and 15-HPETE. These pathways lead to the leukotriene 12-hydroxyeicosatetraenoic acid (12-HETE) and to the lipoxins, respectively. [http://www.mercksource.com/pp/us/cns/cns_hl_dorlands.jspzQzpgzEzzSzppdocszSzuszSzcommonzSzdorlandszSzdorlandzSzdmd_a_56zPzhtm#12148909 Dorlands Medical Dictionary] , entries at "arachidonate 5-lipoxygenase" and following. Retrieved on 2006-02-07.]

Clinical significance

5-LO is a target for pharmaceutical intervention in CAD.cite web |url=http://www.research.ucla.edu/tech/ucla01-429.htm |archiveurl=http://web.archive.org/web/20060830025600/http://www.research.ucla.edu/tech/ucla01-429.htm |archivedate=2006-08-30 |title=5-Lipoxygenase, A New Therapeutic And Diagnostic Target For Heart Disease Management |accessdate=2007-11-18 |publisher=UCLA Case No. 2001-429 PCT Publication Number: WO 03/035670 A2] Some people with variant alleles for 5-LO are at elevated risk for CAD.cite journal |author=Dwyer JH, Allayee H, Dwyer KM, "et al" |title=Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis |journal=N. Engl. J. Med. |volume=350 |issue=1 |pages=29–37 |year=2004 |pmid=14702425 |doi=10.1056/NEJMoa025079] 5-LO is expressed in brain cells and may participate in neuropathologic processes. [cite journal |author=Zhang L, Zhang WP, Hu H, "et al" |title=Expression patterns of 5-lipoxygenase in human brain with traumatic injury and astrocytoma |journal=Neuropathology : official journal of the Japanese Society of Neuropathology |volume=26 |issue=2 |pages=99–106 |year=2006 |pmid=16708542 |doi=10.1111/j.1440-1789.2006.00658.x]

Mutations in the promoter region of this gene lead to a diminished response to antileukotriene drugs used in the treatment of asthma and may also be associated with atherosclerosis and several cancers. Alternatively spliced transcript variants have been observed, but their full-length nature has not been determined. [cite web | title = Entrez Gene: ALOX5 arachidonate 5-lipoxygenase| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=240| accessdate = ]

5-LO inhibitors

As leukotrienes are important causes of pathological symptoms in asthma, 5-LO inhibitors were developed as asthma treatments. The only 5-LO inhibitor currently licensed for human use in asthma is Zileuton.
Minocycline, although primarily a tetracycline antibiotic, is also a 5-LO inhibitor. can be used as DMARDS.cite journal | author=Song Y, Wei EQ, Zhang WP, Zhang L, Liu JR, Chen Z | title=Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation | journal=Neuroreport | year=2004 | pages=2181–4 | volume=15 | issue=14 | pmid=15371729 | doi=10.1097/00001756-200410050-00007 ] It may therefore be used as a DMARD-medication in mild rheumatoid arthritis and other rheumatic conditions. [ [http://arthritis.about.com/od/minocin/Minocin_Minocycline_Dosage_Side_Effects_Drug_Interactions.htm arthritis.about.com: Minocin - Minocycline - Dosage - Side Effects - Drug Interactions] ]

Activation

5-LO is activated by 5-lipoxygenase activating protein (FLAP).

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Rådmark OP |title=The molecular biology and regulation of 5-lipoxygenase. |journal=Am. J. Respir. Crit. Care Med. |volume=161 |issue= 2 Pt 2 |pages= S11–5 |year= 2000 |pmid= 10673219 |doi=
*cite journal | author=Hammarberg T, Reddy KV, Persson B, Rådmark O |title=Calcium binding to 5-lipoxygenase. |journal=Adv. Exp. Med. Biol. |volume=507 |issue= |pages= 117–21 |year= 2003 |pmid= 12664574 |doi=
*cite journal | author=Ishii S, Noguchi M, Miyano M, "et al." |title=Mutagenesis studies on the amino acid residues involved in the iron-binding and the activity of human 5-lipoxygenase. |journal=Biochem. Biophys. Res. Commun. |volume=182 |issue= 3 |pages= 1482–90 |year= 1992 |pmid= 1540191 |doi=
*cite journal | author=Nguyen T, Falgueyret JP, Abramovitz M, Riendeau D |title=Evaluation of the role of conserved His and Met residues among lipoxygenases by site-directed mutagenesis of recombinant human 5-lipoxygenase. |journal=J. Biol. Chem. |volume=266 |issue= 32 |pages= 22057–62 |year= 1991 |pmid= 1939225 |doi=
*cite journal | author=Hoshiko S, Rådmark O, Samuelsson B |title=Characterization of the human 5-lipoxygenase gene promoter. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=87 |issue= 23 |pages= 9073–7 |year= 1991 |pmid= 2251250 |doi=
*cite journal | author=Funk CD, Hoshiko S, Matsumoto T, "et al." |title=Characterization of the human 5-lipoxygenase gene. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue= 8 |pages= 2587–91 |year= 1989 |pmid= 2565035 |doi=
*cite journal | author=Matsumoto T, Funk CD, Rådmark O, "et al." |title=Molecular cloning and amino acid sequence of human 5-lipoxygenase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 1 |pages= 26–30 |year= 1988 |pmid= 2829172 |doi=
*cite journal | author=Rouzer CA, Kargman S |title=Translocation of 5-lipoxygenase to the membrane in human leukocytes challenged with ionophore A23187. |journal=J. Biol. Chem. |volume=263 |issue= 22 |pages= 10980–8 |year= 1988 |pmid= 3134355 |doi=
*cite journal | author=Dixon RA, Jones RE, Diehl RE, "et al." |title=Cloning of the cDNA for human 5-lipoxygenase. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 2 |pages= 416–20 |year= 1988 |pmid= 3422434 |doi=
*cite journal | author=Jakobsson PJ, Shaskin P, Larsson P, "et al." |title=Studies on the regulation and localization of 5-lipoxygenase in human B-lymphocytes. |journal=Eur. J. Biochem. |volume=232 |issue= 1 |pages= 37–46 |year= 1995 |pmid= 7556168 |doi=
*cite journal | author=Janssen-Timmen U, Vickers PJ, Wittig U, "et al." |title=Expression of 5-lipoxygenase in differentiating human skin keratinocytes. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=92 |issue= 15 |pages= 6966–70 |year= 1995 |pmid= 7624354 |doi=
*cite journal | author=Lepley RA, Fitzpatrick FA |title=5-Lipoxygenase contains a functional Src homology 3-binding motif that interacts with the Src homology 3 domain of Grb2 and cytoskeletal proteins. |journal=J. Biol. Chem. |volume=269 |issue= 39 |pages= 24163–8 |year= 1994 |pmid= 7929073 |doi=
*cite journal | author=Shaw KJ, Ng C, Kovacs BW |title=Cyclooxygenase gene expression in human endometrium and decidua. |journal=Prostaglandins Leukot. Essent. Fatty Acids |volume=50 |issue= 5 |pages= 239–43 |year= 1994 |pmid= 8066098 |doi=
*cite journal | author=Maruyama K, Sugano S |title=Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. |journal=Gene |volume=138 |issue= 1-2 |pages= 171–4 |year= 1994 |pmid= 8125298 |doi=
*cite journal | author=Woods JW, Evans JF, Ethier D, "et al." |title=5-lipoxygenase and 5-lipoxygenase-activating protein are localized in the nuclear envelope of activated human leukocytes. |journal=J. Exp. Med. |volume=178 |issue= 6 |pages= 1935–46 |year= 1993 |pmid= 8245774 |doi=
*cite journal | author=Mancini JA, Li C, Vickers PJ |title=5-Lipoxygenase activity in the human pancreas. |journal=Journal of lipid mediators |volume=8 |issue= 3 |pages= 145–50 |year= 1994 |pmid= 8268460 |doi=
*cite journal | author=VanderNoot VA, Fitzpatrick FA |title=Competitive binding assay of src homology domain 3 interactions between 5-lipoxygenase and growth factor receptor binding protein 2. |journal=Anal. Biochem. |volume=230 |issue= 1 |pages= 108–14 |year= 1996 |pmid= 8585605 |doi= 10.1006/abio.1995.1444
*cite journal | author=Brock TG, McNish RW, Bailie MB, Peters-Golden M |title=Rapid import of cytosolic 5-lipoxygenase into the nucleus of neutrophils after in vivo recruitment and in vitro adherence. |journal=J. Biol. Chem. |volume=272 |issue= 13 |pages= 8276–80 |year= 1997 |pmid= 9079648 |doi=
*cite journal | author=Nassar GM, Montero A, Fukunaga M, Badr KF |title=Contrasting effects of proinflammatory and T-helper lymphocyte subset-2 cytokines on the 5-lipoxygenase pathway in monocytes. |journal=Kidney Int. |volume=51 |issue= 5 |pages= 1520–8 |year= 1997 |pmid= 9150468 |doi=
*cite journal | author=Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, "et al." |title=Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library. |journal=Gene |volume=200 |issue= 1-2 |pages= 149–56 |year= 1997 |pmid= 9373149 |doi=

External links

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